Arsenic has been classified as a known human carcinogen of the skin, lung and urinary bladder, however, the mechanisms involved in carcinogenesis by arsenic are not known, due in part to a lack of appropriate animal models. Ongoing studies in our laboratory have suggested that arsenic serves as a tumor enhancer or progressor in the skin of Tg.AC transgenic mice via stimulation of the chronic production of cytokines and growth factors, including granulocyte macrophage colongy stimulating factor, transforming growth factor alpha and tumor necrosis factor alpha. In the past year, we have begun to investigate inter-individual variation in responses to arsenic, to address the question of why some individuals or populations appear to be less sensitive to arsenic-induced toxicities. We have examined the cytokine profiles produced by several different normal human keratinocyte donors in response to arsenic treatment via ELISA and RT-PCR, and have shown that while cytokine responses are qualitatively similar, in that similar cytokines are produced, sensitivity to dose and quantitative cytokine secretion vary from donor to donor. In collaboration with Dr. Miroslav Styblo we are examining whether the differential sensitivity seen with various keratinocyte donors may be a reflection of their ability to methylate arsenic. To further confirm this we are examining the toxicity of both trivalent and pentavalent arsenicals in keratinocyte cultures. As hypersensitivity responses are highly dependent on cytokine secretion and regulation, and as we have previously demonstrated that growth and inflammatory cytokines are modulated by arsenic exposure, we are in the process examining how low level arsenic exposure modulates hypersensitivity responses in Balb/c mice. In arsenic-exposed mice antigen-specific proliferative responses to sensitizing agents such as dintrofluorobenzene and hexacinnamaldehyde are significantly reduced. In contrast, mitogen-stimulated proliferative responses in the draining lymph nodes were not affected by arsenic exposure. The potential mechanisms of these alterations, including determination of arsenic effects on migration of Langerhans cells to the draining lymph node, possible alterations in MHC class II expression and/or antigen presentation and modulation of the expression of regulatory cytokines is currently under investigation. This project was previously reported as part of Z01 ES 30106 23 LT